CASE STUDIES FROM NEURONEXT

CASE STUDIES FROM NEURONEXT

Christopher S. CoffeyDepartment of Biostatistics

University of Iowa

Source: PhRMA, 2008

High levels of risk, uncertainty, & complexityOnly 11% of drugs that enter clinical testing will be

approved in US

OVERVIEW

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Three basic requirements for any clinical trial:

1) Trial should examine an important research question

2) Trial should use rigorous methodology to answer the question of interest

3) Trial must be based on ethical considerations and assure that risks to subjects are minimized

Due to size limitations, meeting these requirements in early phase clinical trials can be a challenge.As a consequence, the importance of study planning is magnified in these settings. 3

OBJECTIVES

Fundamental Point: Every clinical trial must have one or more primary

question(s). Should be of interest, and one that is capable of

being answered. Question on which sample size should be based Primary question(s) should be:

• Carefully selected• Clearly defined• Stated in advance

OBJECTIVES

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Key Aspect - What is the Question? Phrase research question in concise, quantitative

terms Poor Question:

“Is drug A better than drug B” Better Question:

“In population W, is drug A at daily dose X more efficacious in reducing Z over a period of time T

than drug B at daily dose Y?”

OBJECTIVES

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Each objective should link to a primary endpoint(s)This response variable will be compared across interventions in order to answer the primary question of interest.Necessary properties:

• Reflects primary objective of trial• Able to measure in all study subjects• Specified before trial is started• As objective as possible

OBJECTIVES

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Secondary Objectives: Need to be defined a priori (avoid post hoc “fishing

expedition”) Chosen parsimoniously (avoid false positives) Two broad types:

• Examine response variable different from primary endpoint

• Subgroup hypotheses

OBJECTIVES

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Common Errors in Drug Development:Poorly designed and optimistically interpreted “proof

of concept” studies Insufficient exploration of dose, regimen, and route

of administrationProceeding to phase III without adequate early

phase data to guide study design• Population; Sample Size; Endpoints; Study Duration

Ignoring FDA advice regarding evidence necessary to support a marketing application

OBJECTIVES

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Phase I Trials: First investigation of potential new drug in humans Conducted in small number of healthy volunteers Results guide dosing and monitoring of future trials Objectives:

• Safety – Assess most significant adverse events• Tolerability – Explore possible toxic effects &

determine a maximum tolerated dose• Pharmacokinetics – Study of how drug is absorbed,

metabolized, and eliminated from body• Pharmacodynamics – Study of biochemical &

physiological effects of drug on body

PHASE I STUDIES

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PHASE I STUDIES

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Early learning phase designs in areas with potentially toxic treatments (e.g. cancer/neurological diseases) seek to determine the maximum tolerated dose (MTD).MTD is highest dose of drug that can be given before some percent of subjects experience an unacceptable dose limiting toxicity (DLT).

If Y denotes binary response with Y=1 denoting occurrence of DLT, and q0 denotes toxicity limit, then we seek to find a dose XMTD where:

Pr( Y=1 | XMTD) = q0

PHASE I STUDIES

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Accurate determination of the MTD is critical, since it will likely be used as the maximum dose in future clinical development. If dose too low, could miss potentially useful drug If dose too high, participants in future studies could

be put at riskGenerally interested in toxicityvalues between 10%-40%

Generally desired to proceed very cautiously: Begin with small doses

• Well below dose expected to cause toxicity• But, also likely well below effective dose

Enroll in small cohorts (1-3 subjects) Any given dose escalation cannot increase by

more than one level• Ethical conflict is to increase dose slowly to avoid

unacceptable toxicity, but quickly enough to provide a therapeutic benefit

PHASE I STUDIES

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PHASE I STUDIES

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Conventional 3+3 methods, developed for oncology settings, employ an ad-hoc approach to identify MTD.Subjects are treated in groups of three, starting at initial low doseAlgorithm iterates moving dose up or down depending on number of toxicities observedThe MTD is identified from the data – highest dose studied with less than 2 toxicities out of a maximum of six treated patients.

PHASE I STUDIES

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Bayesian paradigm allows incorporating ethical and statistical concerns from pre-clinical studies and sources outside of trial. Quantify prior information and uncertainty into a

probability distribution Update information and easily implement a

sequential design strategy Use all data to model dose-toxicity curve Most common approach is Continual

Reassessment Method [CRM – See Garrett-Meyer (Stat Med, 2005) for excellent tutorial]

Desired Study Parameters: Placebo group included for secondary comparison

of intracranial bleeding rates Enroll approximately 100 subjects

• 88 subjects in groups of four (3 treated / 1 placebo)• Default to placebo during safety review pauses

Dose limiting toxicities (DLTs) assessed from first dose to 48 hours following last dose of study treatment

NEURONEXT NN104 STUDY

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Dose Levels: Four dose levels under consideration (dose level

can’t be increased by > one level at a time)• 120 µg/kg• 360 µg/kg

Target Toxicity Rate: MTD defined as highest dose with an estimated

dose limiting toxicity (DLT) rate of 10% or lessDesign: Continual Reassessment Method

• 240 µg/kg• 540 µg/kg


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CRM model proceeds as follows:1) Enroll 4 subjects (3 treatment / 1 placebo) into a

cohort2) Determine # of evaluable subjects in cohort3) Observe # of evaluable subjects (out of 3 treated)

that have a DLT per study definition4) Refit dose-response curve using observed

information from all evaluable subjects to date5) Continue until pre-defined stopping criteria met

ADAPTIVE DOSE FINDING

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No DLTs observed, estimated curve

substantially lower -- all doses < 10%.

But, since dose can only increase by one level, cohort 2 treated at 240

μg/kg

CohortDose

(μg/kg)Evaluable Subjects

# of DLTs

Toxicity Estimates

120 240 360 540

5% 7% 9% 11%

1 120 3 0 1% 2% 3% 4%


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DLT (Cerebral Hemorrhage) observed in subject treated

with 240 μg/kgAll DLT estimates now above 10% threshold.

Cohort 3 treated at 120 μg/kg

CohortDose

(μg/kg)Evaluable Subjects

# of DLTs

Toxicity Estimates

120 240 360 540

5% 7% 9% 11%

1 120 3 0 1% 2% 3% 4%

2 240 3 1 11% 14% 17% 20%


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540 μg/kg is the maximum tolerated dose, with an estimated DLT rate around 7%


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Phase II Trials: Performed in patients with disease of interest In general, phase II trials may be smaller than they

should be Results guide design of subsequent confirmatory

(phase III) trial

PHASE II STUDIES

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Confirmatory Designs:• Large sample sizes

• Many standard designs

Learning Stage Designs:• Efficiency is critical

• Carefully evaluate alternative designs

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PHASE II STUDIES

PHASE II STUDIES

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Main Goals: Provide assessment of preliminary efficacy

• Screen out ineffective treatments• Determine if new treatment is sufficiently promising to

justify inclusion in large-scale randomized trials

Further characterize the safety profile Avoid early phase designs that look to simply

be an underpowered phase III study• “Treatment Effects” estimated in pilot studies often

tend to be over-estimates of true effect

PHASE II STUDIES

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Due to concerns about missing an important effect, researchers may be tempted to include a large number of endpoints. If study design often calls for “going forward” if any

endpoint shows hint of an effect, then this type of design will almost always “go forward” – even if treatment does not work

Due to business implications, early phase studies with positive findings are more likely to be highlighted – could be real effect or ‘chance’ finding

PHASE II STUDIES

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Due to budgetary constraints, researchers may insist on sample size limitations, regardless of whether there is scientific justification. Study may not be able to adequately answer

question of interest Results become somewhat subjective

• A researcher who views treatment favorably will likely see positive trends

• A researcher who views treatment unfavorably will likely see negative trends

Types of Phase II Studies: Using Different Endpoints Than Phase III Endpoint

• Safety/Tolerability Designs• Surrogate Endpoint Designs

Using Phase III Endpoints – Not Powered for Efficacy (in Phase III sense)

• Predictive Probability Designs• N-of-1 Designs• Selection Designs• Futility Designs

PHASE II STUDIES

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SAFETY/TOLERABILITY DESIGNPossible to design a trial to primarily address safety & tolerability.Trial powered to detect some specified level of

safety concerns (usually higher than level of minimal concern)

Trial also power to detect important differences in tolerability (completing study on assigned dose)

Efficacy data typically collected as an exploratory outcome

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NN-105 STAIR Study: Primary Objective:

To assess the tolerability of SRX246 in irritable subjects with early symptomatic HD over a period of 12 weeks compared to placebo


Rand

omize

ScreeningPhase

Initial Screening

120 mg(n = 36)

Placebo(n = 36)

160 mg(n = 36)

(Up to 30 days)

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Primary Tolerability Hypothesis:Assess whether either 120 mg or 160 mg daily

dosing of SRX246 is sufficiently tolerable, compared to placebo.• Assessed by comparing percentage of participants

enrolled in each dosage group who are able to complete study (12 weeks) on assigned dose Any participant removed from study drug or who fails to complete

the study (for any reason) will be deemed not to have tolerated their assigned medication

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SURROGATE ENDPOINT DESIGNAs previously discussed, a surrogate endpoint (biomarker) can be measured earlier, easier, and more frequently than many standard clinical endpoints.

A surrogate endpoint design allows using surrogate for ‘go’ / ‘no go’ decision making.

This often leads to reduced sample size or length of study – allowing screening process to move more efficiently.

Subsequent confirmatory studies can still be powered on the gold standard clinical endpoint.

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NN-102 SPRINT-MS Study: A Randomized, Double-Blind, Placebo-Controlled

Study to Evaluate Safety, Tolerability, and Activity of Ibudilast (MN-166) in Subjects with Progressive Multiple Sclerosis• PI: Robert Fox (Cleveland Clinic)

• Primary Objective:To evaluate the activity, safety, and tolerability of ibudilast(MN-166 – 100 mg/day) versus placebo administeredorally in subjects with primary progressive andsecondary progressive multiple sclerosis


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NN102: SPRINT-MS Study In a phase 2 trial involving patients

with progressive MS, ibudilast wasassociated with slower progressionof brain atrophy than placebo

Ibudilast was associated with higherrates of gastrointestinal side effects,headache, and depression


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Trends toward similar benefit on clinical endpoint of disease progression.

Needs to be confirmed in a larger, confirmatory trial


HR = 0.74 w/ 90% CI of (0.47,1.17); p = 0.24

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FUTILITY DESIGNA futility (non-superiority) design is a screening tool to identify whether agents should be candidates for phase III trials while minimizing costs/sample size. If “futility” is declared, results would imply not cost

effective to conduct a future phase III trial If “futility” is not declared, suggests that there could

be a clinically meaningful effect which should be explored in a larger, phase III trial

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Statistical Properties:

NullHypothesis

(H0)

AlternativeHypothesis

(HA)

Rejecting H0

Type I Error

(α)

Type II Error

(β)

UsualDesign μT = μP

μT ≠ μP

New Treatment is Effective(Harmful)

Ineffective Therapy is Effective

Effective Therapy is Ineffective

FutilityDesign μT – μP ≥ 0 μT – μP < 0

New Treatment is Futile

EffectiveTherapy is Ineffective

Ineffective Therapy is Effective

FUTILITY DESIGN

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Thus, futility designs are good at identifying ineffective treatments, but not very good at identifying effective treatments.

However, improvement over running underpowered efficacy trials in phase II or conducting phase III trials as first rigorous test of efficacy for a new treatment.

FUTILITY DESIGN

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High negative predictive values:If “futility” declared, treatment likely not effective

Low positive predictive values:Lack of “futility” does not imply treatment is effective

NN-103 - BeatMG• PI: Richard Nowak (Yale)• A previous study at Yale demonstrated that ~80% of subjects

treated with rituximab achieved at least a 75% reduction in their prednisone dose at 52 weeks

• Primary Objective: Determine whether large benefit observed in prior Yale study can be refuted in a multi-site trial, or looks promising enough to justify a future phase III trial (“go”)


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Suppose a 30% increase in favorable response rates (achieving a 75% reduction in prednisone dose) with rituximab over placebo is clinically meaningful.This futility design tests the following hypothesis:

H0: Rituximab improves outcome by at least 30% compared to placebo(pR – pP ≥ 0.30 – not futile)

versus

HA: Rituximab does not improve outcome by at least 30% copmared to placebo

(pR – pP < 0.30 – futile)


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Power to declare “futility” for range of true response rates for rituximab (assumes placebo rate of 40%):

Table demonstrates benefits of using futility design, if true rituximab success rate: Near/below placebo rate, declare “futility” with high probability

Well above placebo rate, low probability of declaring “futility”

In between, uncertainty to address in subsequent trial

RituximabRate (pR) 30% 35% 40% 45% 50% 60% 70% 80% 90%

Pr (Futility) 92% 84% 74% 63% 50% 25% 10% 2% <1%


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Reduction in Mean Daily Prednisone

Dose ≥ 75%

1-Sided Odds Ratios (90% CI) Rituximab vs.

PlaceboGroup Rituximab Placebo

Primary 60% 56% 1.14 (0 , 2.41)Observed 65% 63% 1.11 (0 , 2.43)

Primary results show “futility” for showing pre-defined clinically meaningful difference with rituximab (p = 0.03).


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CASE STUDIES FROM NEURONEXT